Proefschrift_Holstein

Dopamine D2 receptors and cognitive flexibility

sulpiride increased plasma prolactin levels relative to placebo ( supplementary results: table S3.1 ). These data evidence the opposite effects of the two drugs in vivo. The finding that the prolactin response was not nullified in the combined sulpiride and bromocriptine session (sulpiride versus sulpiride and bromocriptine: t (21) = -.279, p = .783) likely reflects the fact that sulpiride was administered prior to bromocriptine. The effect of sulpiride was disproportionately large, thus masking any subsequent effect of bromocriptine. Discussion The present results show that the dopamine receptor agonist bromocriptine improved task switching by stimulating dopamine D2 receptors. Specifically, bromocriptine reduced the error switch cost in individuals with genetically determined low dopamine levels, and this beneficial effect of bromocriptine on task switching was abolished by pre-treatment with the selective dopamine D2 receptor antagonist sulpiride. This finding significantly strengthens prior evidence (Mehta et al., 2004; Floresco et al., 2006b; Cools et al., 2007a; Durstewitz and Seamans, 2008; Stelzel et al., 2010) for a role of dopamine D2 receptor signalling in task switching, thus further establishing a role for dopamine outside the domains of working memory and learning in humans. In particular, the data concur with the dual-state theory put forward recently by Durstewitz and Seamans (Seamans and Yang, 2004; Durstewitz and Seamans, 2008), which is grounded in in vitro neurophysiology and biophysically realistic computational modelling work (see introduction). According to this theory, dopamine D2 receptor stimulation favours fast flexible switching between different task-relevant representations, by allowing multiple inputs to impinge simultaneously on the PFC. It also fits with data from animal studies showing that genetic over-expression of striatal dopamine D2 receptors (Kellendonk et al., 2006) and abnormal increases in dopamine D2 receptor activity in the rodent striatum alters strategy set shifting in rodents (Haluk and Floresco, 2009). It might be noted that the present finding that the beneficial effect of bromocriptine on task switching was blocked by pre-treatment with sulpiride highlights the role of dopamine D2 receptor signalling in task switching, but does not directly rule out the involvement of dopamine D1 receptor signalling or the importance of synergistic action between dopamine D1 and D2 receptor signalling in task switching. Indeed rodent work suggests that both dopamine D1 and D2 receptor signalling are important for cognitive flexibility (Floresco et al., 2006b). The conclusion that task switching implicates dopamine D2, but not D1 receptor signalling would require demonstration that effects of bromocriptine were not blocked by a dopamine D1 receptor antagonist. Unfortunately, there is a relative lack of dopamine D1 selective drugs available for human research, and accordingly, such a demonstration will have to await future developments. An interesting feature of current dual-state theory is that the beneficial effect of dopamine D2 receptor stimulation on task switching might be accompanied by a detrimental effect on the stabilization of current task-relevant representations. This hypothesis is corroborated here by

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